The long-term goal of this proposal is to define the mechanism responsible for the reduced maximal exercise capacity of patients with heart failure. Prior observations suggest that this exercise intolerance is caused by underperfusion of skeletal muscle with resultant early muscle glycolysis and that the muscle underperfusion is due at least in part to impaired muscle arteriolar dilation. This proposal's specific objectives are 1) to clarify the prevalence of and mechanisms for impaired muscle arteriolar vasodilation in heart failure, 2) to determine if early muscle glycolysis in heart failure is due to a reduction in muscle O2 delivery and/or muscle oxidative capacity, and 3) to determine if muscle fatigue is due to muscle lactic acidosis. Muscle arteriolar behavior during exercise will be compared in patients with heart failure and normal subjects during forearm exercise and maximal bicycle exercise. Plethysmography will be used to measure forearm flow. A femoral venous thermodilution catheter will be used to measure leg flow. Muscle arteriolar behavior will be further characterized by examining maximal forearm vasodilatory capacity, forearm vascular responsiveness to intraarterial norepinephrine and angiotensin II, and forearm vascular responses to diuresis, digitalis and chronic angiotensin-converting enzyme inhibition. To clarify the relation of muscle metabolism to O2 delivery and muscle oxidative capacity, forearm flow will be correlated with forearm metabolism, measured with 31P NMR. The effect of increasing muscle O2 delivery on exercising forearm and leg muscles will be examined. Skeletal muscle biopsies will be analyzed for enzyme activities, capillarity and fiber type. To determine if lactate limits exercise, the effect of reducing muscle lactate accumulation with dichloroacetate will be examined. Parallel dog studies will be performed in a canine model of heart failure produced by chronic rapid ventricular pacing. Skeletal muscle arteriolar behavior will be assessed in the femoral bed during treadmill exercise and in an isolated gracilis muscle preparation. Arteriolar vasodilation during exercise, vascular responsiveness and the contributions of sodium retention, sympathetic activity and angiotensin II to altered arteriolar behavior will be examined. Skeletal muscle biopsies and dichloroacetate will be used to study muscle enzymatic changes and the contribution of lactate to exercise intolerance. These studies should help to clarify the mechanism responsible for the reduced maximal exercise capacity of patients with heart failure.